Prostaglandin e receptor antagonists

Abstract

The present invention provides prostaglandin receptor antagonist compounds represented by the general formula I, wherein A, R, R 1 and R 2 are as defined in the specification.

1 . A compound having prostaglandin receptor antagonist activity represented by the general formula I. 
       
         
           
           
               
               
           
         
       
       Wherein R is R 3 —C(O)CH 2 —CH(OH)(CH 2 OH) or R 3 —C(O)CH(CH 2 OH) 2  and R 3  is selected from the group consisting of O, NR 4 , S and C(R 5 ) 2    
       wherein R 4  represents a radical selected from the group consisting of H, hydrocarbyl and heteroatom-substituted hydrocarbyl radicals, wherein said hetero atom is selected from the group consisting of halogen, O, S and N, i.e. O, S and/or N may be included as a O, S, or N-containing radical and R 5  represents a radical selected from the group consisting of H, hydrocarbyl and heteroatom-substituted hydrocarbyl radicals, wherein said hetero atom is selected from the group consisting of halogen, O, S and N, i.e. O, S and/or N may be included as a O, S, or N-containing radical;
 m is an integer of from 1 to 3; 
 n is 0 or an integer of from 1 to 4; 
 A is an aryl or heteroaryl radical having from 6 to 14 carbon atoms, wherein said heteroaryl may be substituted with one or more oxygen, sulfur or nitrogen in the heteroaryl ring and heteroatom substituted derivatives thereof; 
 R 1  and R 2  are independently selected from the group consisting of H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 7  cycloalkyl, C 4 -C 12  alkylcycloalkyl, C 6 -C 10  aryl, C 7 -C 12  alkylaryl radicals and heteroatom-substituted derivatives thereof, wherein one or more of the hydrogen or carbon atoms in said radicals may be replaced with a halogen, oxygen, nitrogen or sulfur-containing radical; and pharmaceutically acceptable salts thereof. 
 
     
     
         2 . The compounds of  claim 1  represented by formula II 
       
         
           
           
               
               
           
         
       
       wherein X is selected from the group consisting of H, C 1 -C 6  alkyl, hydroxyl, halogen, COOR 6 , NO 2 , CF 3 , N(R 6 ) 2 , CON(R 6 ) 2 , SR 6 , sulfoxy, sulfone, CN and OR 6 , wherein R 6  is H or C 1 -C 6  alkyl. 
     
     
         3 . The compounds of  claim 2  wherein m is 1 or 2. 
     
     
         4 . The compounds of  claim 2  wherein n is from 2 to 4. 
     
     
         5 . The compounds of  claim 2  wherein R 1  and R 2  are selected from the group consisting of H, C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl and C 4 -C 12  alkylcycloalkyl. 
     
     
         6 . The compounds of  claim 2  wherein X is hydrogen or halogen. 
     
     
         7 . The compounds of  claim 6  wherein X is fluoro. 
     
     
         8 . The compounds of  claim 1  represented by formula III 
       
         
           
           
               
               
           
         
       
       wherein Y is O or S, Z is N or CH and wherein X is selected from the group consisting of H, C 1 -C 6  alkyl, hydroxyl, halogen, COOR 6 , NO 2 , N(R 6 ) 2 , CON(R 6 ) 2 , SR 6 , sulfoxy, sulfone, CN and OR 6 , wherein R 6  is C 1 -C 6  alkyl. 
     
     
         9 . The compound of  claim 8  wherein m is 1 or 2. 
     
     
         10 . The compound of  claim 8  wherein n is 2 to 4. 
     
     
         11 . The compound of  claim 8  wherein R 1  and R 2  are selected from the group consisting of H, C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl and C 4 -C 12  alkylcycloalkyl. 
     
     
         12 . The compound of  claim 8  wherein X is hydrogen or halogen. 
     
     
         13 . The compound of  claim 12  wherein X is fluoro. 
     
     
         14 . The compound of  claim 1  wherein the compound is 3-(2-{(1R,2R,3S,4R)-3-[4-(4-Cyclohexyl-butylcarbamoyl)-oxazol-2-yl]-7-oxa-bicyclo[2.2.1]hept-2-ylmethyl}-4-fluoro-phenyl)-propionic acid, 1,3-dihydroxyprop-2-yl ester. 
     
     
         15 . The compound of  claim 1  wherein the compound is 3-(2-{(1R,2R,3S,4R)-3-[4-(4-Cyclohexyl-butylcarbamoyl)-oxazol-2-yl]-7-oxa-bicyclo[2.2.1]hept-2-ylmethyl}-4-fluoro-phenyl)-1,3-dihydroxyprop-2-yl-propionamide. 
     
     
         16 . The compound of  claim 1  wherein the compound is 3-(2-{(1R,2R,3S,4R)-3-[4-(4-Cyclohexyl-butylcarbamoyl)-oxazol-2-yl]-7-oxa-bicyclo[2.2.1]hept-2-ylmethyl}-4-fluoro-phenyl)-propionic acid, 1,2-dihydroxyprop-3-yl ester. 
     
     
         17 . The compound according to  claim 1  wherein the compound is: